This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gonadal neurosteroids are important modulators of behavior and have been shown to impact a range of clinically significant conditions, including sexual behavior, sleep, cognition, drug and alcohol abuse, affective disorders, pain sensitivity, epileptic seizure disorders and stress reactivity. Recent molecular and cellular studies as well as data from whole animal behavioral models indicate that gonadal neurosteroids influence behavior through the direct regulation of neuronal activity, as well as the modulation of classical neurotransmitter function, through a variety of both genonic and nongenomic mechanisms. To date, the effects of estrogen and progesterone on neurotransmitter function in humans have received almost no attention. We, and others, have successfully used drug discrimination and functional neuroimaging methodologies to examine the manner in which psychoactive drugs alter classical neurotransmitter function (i.e., clinical neuropharmacological effects of drugs), as well as the neuroanatomical locations of these effects. This basic science project will be among the first to apply these methodologies within the same individuals to examine the manner and anatomical locations in which estrogen and progesterone modulate clinical neurotransmitter function in humans. One series of studies will examine the effects of estradiol on dopaminergic activity. It is hypothesized that estradiol will enhance dopamine function selectively in women. A second series of studies will examine the neuropharmacological effects of progesterone. It is hypothesized that progesterone and its metabolites will engender direct interoceptive effects via modulation of multiple receptor sites, including GABA alpha and NMDA, in both men and women. This information will be invaluable for expanding our understanding of the neurobiological basis of gender differences in mood and behavior regulation. These studies will have important applied significance in helping future development of gender-specific medications having selective effects at steroidal receptor sites and/or tailored to work in combination with endogenous neurosteroids. It is also likely that these studies will inform and enhance ongoing efforts to develop and evaluate steroid-based medications. Finally, this project will promote the mentoring, development and promotion of our junior and early career colleagues'academic interests in the clinical neurobiology of women's health.